This document summarizes key concepts in pharmacodynamics including: - Mechanisms of drug action including receptor interactions, dose effects, and therapeutic/toxic effects - Definitions of terms like agonist, antagonist, affinity, potency, efficacy - Mechanisms of signal transduction between drug binding and intracellular effects - Types of drug targets including receptors, ion channels, enzymes, and carriers - Concepts of drug-receptor binding and interactions, dose-response curves, and agonists vs antagonists - Factors influencing drug properties like safety, interactions, adverse effects, toxicity, idiosyncrasies, and tolerance

1. Pharmacodynamics

2. Pharmacodynamics Pharmacodynamics – deals with the action of a drug on the body; what the drug does to the body; Mechanisms of Drug Action on the bory: Receptor interactions Dose-related phenomena Therapeutic action Toxic effects

3. Definitions Agonist – drug that triggers the same events as the native ligand when it binds to a receptor Antagonist – drug that prevents binding of the native ligand to the receptor so that it cannot produce its normal action Affinity – ability of a drug to bind to a receptor (how well a drug & a receptor recognize each other) Potency – quantity of a drug needed to achieve a desired effect; more potent, lower EC 50 Quality – bioavailability of the drug Efficacy – maximal effect an Agonist can achieve at the highest practical concentration ( a measure of how well a drug produces a response); high Emax

4. Definitions 2 nd messenger – small nonprotein water-soluble molecule or ion that readily spreads a ‘signal’ throughout the cell by diffusion (e.g. cyclic AMP; Calcium ions) Signal transduction – process by which extracellular inputs (e.g. drug-receptor interactions) lead to intracellular messages that moderate cell physiology sequencing

5. Mechanisms of Signal Transduction 1 – Drug crosses the cell membrane, activates an intracellular receptor e.g. steroid hormones 2 – transmembrane receptor protein with intracellular enzyme activity is affected by a drug binding to a site on the enzyme that can alter its activity e.g. Ouabain 3 – A drug-transmembrane receptor protein complex binds & stimulates a 2 nd protein such as Tyrosine kinase 4 – A drug binding to a transmembrane ion channel changes ion conductance, affecting membrane potentials e.g. nicotinic ACh receptor stimulation 5 – An agonist drug binds to a transmembrane receptor, stimulating a G protein, leading to increased intracellular 2 nd messengers that result in many 2 ºintracellular responses e.g. adrenergic stimulation

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8. G protein Signal transduction 5

9. Benefits of a Signal Transduction Pathway Signal amplification Increased cellular processes Proteins persist in active form long enough to process numerous molecules of substrate Each step activates more products than the preceding step Signal specificity Specific cellular components (& therefore specific cellular processes) are affected

10. Drug Binding Covalent bonds – sharing of a pair of electrons between 2 atoms; very stable, very strong- requires hundreds of kilojoules to disrupt nonCovalent bonds – generally weak – Hydrogen bonds Van der Waals forces Ionic / Electrostatic interactions Hydrophobic interactions Effects of Binding : Conformation – binding locks a mobile flexible molecule into a restricted conformation Configuration / Stereochemistry – change may alter biologic effects

11. Targets for Drug Action “ A drug will exert its activity through interactions at one or more molecular targets – macromolecular species that control the function of cells: surface-bound receptors & ion channels or internal structures like enzymes & nucleic acids” Targets for Drug action: Processes of Drug Action: Receptors *chemical Ion channels *enzymatic Enzymes *thru receptors Carriers * thru ion channels *thru 2 nd messengers

12. Receptor targets for Drug Action Chlorpromazine Dopamine Dopamine2 receptor Ketanserin 5 HT 5 HT2 receptor Naloxone Morphine Opiate Propranolol Noradrenalin β blocker Tubocurarine Acetylcholine; Nicotine Nicotinic Ach receptor antagonist agonist receptor

13. Ion channel targets for Drug Action Glycine Dizoclipine, Ketamine Glutamate-gated channel Sulfonylureas ATP ATP-sensitive K channel Benzodiazepines Picrotoxin GABA-gated Cl channel Dihydropyridines Divalent cations Voltage-gated Ca channel Aldosterone Amiloride Renal tubular Na channel Veratridine Local anaesthetics Voltage-gated Na channel Modulators Effectors: blockers Ion channel

14. Enzyme targets for Drug Action Didanosine Reverse transcriptase hemicholinium Choline acetyl transferase Allopurinol Xanthine oxidase Captopril Angiotensin-converting enzyme (ACE) Aspirin cycloOxygenase Neostigmine; Organophosphates Acetylcholinesterase (AChE) False substrates Effectors: inhibitors Enzyme

15. Carrier targets for Drug Action Omeprazole Proton pump in gastric mucosa Cardiac glycoside Na-K pump Probenecid Weak acid carrier Reserpin Noradrenalin uptake ( vesicular ) Amphetamine; Methyldopa TCA; Cocaine Noradrenalin uptake Hemicholinium Choline carrier False substrates Inhibitors Carrier

16. Drug Receptors Drug receptor – macromolecular component of a cell with which a drug interacts to produce a response; usually a protein, a drug interacts with it in a “lock-&-key” fashion, initiating a chain of events that leads to a pharmacologic response. Types of Receptors: Type I : Ionotropic /Ligand-gated ion channels Type II : Metabotropic / coupled to G-protein Type III: Tyrosine Kinase-linked (e.g. Insulin receptor) Type IV: Steroid receptors (e.g. Thyroxine; Cortisol)

17. Protein Receptors Receptors for endogenous regulatory ligands – hormones, growth factors, neurotransmitters; Enzymes of crucial metabolic or regulatory pathways – Acetylcholinesterase, Enzymes in transport processes – Na/K pump; Structural proteins – Tubulin;

18. Drug – Receptor Interactions The binding of a drug to a specific receptor causes some event which leads to a response Response to a drug is graded or dose-dependent Drug-Receptor interactions follow simple mass-action relationships: Only one drug molecule occupies each receptor site Binding is reversible For a given drug, the magnitude of response is directly proportional to the number of receptor sites occupied by drug molecules The number of drug molecules is assumed to be much greater than the number of receptor sites

19. Drug – Receptor Interactions Receptor – specific macromolecule ( Proteins – 90% - membrane, cytoplasmic or extracellular enzyme, nucleic acid; Lipids; Carbohydrates) which is the site of action of most drugs: Only around 10% of drug actions & effects are NOT mediated thru receptors. For most drugs, the magnitude of the pharmacological response increases as the dose (drug concentration) increases Only one drug molecule occupies each receptor site, & binding is reversible

20. The Dissociation Constant The Dissociation Constant – KD – drug concentration at which half maximal binding occurs: the smaller the KD, the greater the affinity of the drug to the receptor; the smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding

21. Log dose – Response curve characteristics: Maximal effect (plateau) Potency – the location of the drug response curve along the horizontal axis: drug effect with respect to dose (vs. Efficacy – maximal ceiling effect) Slope Standing curve – minute changes in dose result in large effects Inclining curve – large changes in dose needed for an effect Variability – the curve is different from drug to drug, from patient to patient, & from time to time in the same patient. So if you want to fix the pharmacologic response at a certain level, you have to use a Range of Dose

22. Log dose – Response Curve Log dose slope potency variability Maximal effect intensity of effect

23. Dose – Response Relationship No drug can create a new effect: a drug only modulates a pre-existing function Drug-receptor interaction leads to enhancement, inhibition, or blockade of molecular signals, which is then amplified thru biochemical & physiologic events to produce the pharmacological (clinical) effect The magnitude of a response is graded, i.e. increases continuously as the concentration of unbound drug increases at the receptor site

24. Definitions GRADED-RESPONSE CURVE : A plot of efficacy (some measured value, such as blood pressure) -vs- drug concentration. EC50 = drug concentration at which 50% efficacy is attained. The lower the EC50, the more potent the drug. Emax = the maximum attained biological response out of the drug. QUANTAL DOSE-RESPONSE CURVE : A graph of discrete (yes-or-no) values, plotting the number of subjects attaining the condition (such as death, or cure from disease) -vs- drug concentration. ED50 : dosage at which 50% of the population attains the desired effect LD50 : dose at which 50% of the population is killed from a drug.

25. Agonists & Antagonists Agonists – drugs that interact with & activate receptors Full agonists – maximal efficacy (Emax) Partial agonists – less than maximal efficacy - At low concentrations, it increases the overall biological response from the receptor. At high concentrations, as all receptors are occupied, it acts as a competitive inhibitor and decreases the overall biological response from the receptor. Antagonists – drugs that prevent the agonists from having an effect by binding to the receptor or to part of the effector mechanism; have no effect themselves

26. Antagonists tend to up-regulate receptors Agonists tend to desensitize receptors Competitive antagonists may be overcome (surmountable) Partial agonist has affinity & (less) intrinsic activity Antagonist has affinity but NO intrinsic activity Agonist has affinity plus intrinsic activity ANTAGONIST AGONIST

27. Inhibition COMPETITIVE INHIBITORS : They bind to the same site as the endogenous molecule, preventing the endogenous molecule from binding. The Dose-Response Curve SHIFTS TO THE RIGHT in the presence of a competitive inhibitor. EC50 is increased: more of a drug would be required to achieve same effect. Emax does not change: maximum efficacy is the same, as long as you have enough of the endogenous molecules around. The effect of a competitive inhibitor is REVERSIBLE and can be overcome by a higher dose of the endogenous substance. The intrinsic activity of a competitive inhibitor is 0 . It has no activity in itself, but only prevents the endogenous substance from having activity.

28. Inhibition NON-COMPETITIVE INHIBITORS : They either (1) bind to a different (allosteric) site, or (2) they bind irreversibly to the primary site. The Dose Response Curve SHIFTS DOWN in the presence of a non-competitive inhibitor. EC50 is increased: more of a drug would be required for same effect. Emax decreases: The non-competitive inhibitor permanently occupies some of the receptors. The maximal attainable response is therefore less. The intrinsic activity of the non-competitive inhibitor is actually a negative number , as the number of functional receptors, and therefore the maximum attainable biological response, is decreased.

29. Properties of a Drug Safety: Therapeutic Index (TI) = LD50 / ED50 The ratio of median lethal dose to median effective dose. The higher the therapeutic index, the better. That means that a higher dose is required for lethality, compared to the dose required to be effective. minimum dose that produces toxicity over the minimum dose that produces an effective therapeutic response; TI < 4 =relatively greater potential for toxicity Margin of Safety = LD1 / ED99 The ratio of the dosage required to kill 1% of population, compared to the dosage that is effective in 99% of population. The higher the margin of safety, the better. greater difference between therapeutic effective dose (ED) & toxic dose (TD)

30. Drug interactions Synergism/Potentiation – concomitant administration of another drug will increase the clinical effect e.g. multi-regimen TB treatment Addition – effects of two drugs administered at the same time will be added to each other e.g. DOLCET Inhibition – simultaneous administration of another drug will decrease the effects of the first e.g. Warfarin & vitamin K Pharmacokinetic interaction – giving of another drug will affect the first’s absorption, distribution, metabolism, &/or excretion

31. Adverse Effects & Drug Interactions Side effect - part of the pharmacologic action of the drug but not the effect the drug is being used for; may be undesirable (adverse) e.g. gastric irritation from NSAIDS Hypersensitivity reactions / Drug Allergy : An exaggerated, immune-mediated response to a drug. TYPE-I : Immediate IgE-mediated anaphylaxis. e.g. Penicillin anaphylaxis .

32. Immunologic Reactions TYPE-II : Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attack against a specific cell type, usually blood cells (e.g. Hemolytic anemia : induced by Penicillin or Methyldopa; Thrombocytopenia : induced by Quinidine; Drug-induced SLE caused by Hydralazine or Procainamide. TYPE-III : Immune-complex drug reaction Serum Sickness: Urticaria, arthralgia, lymphadenopathy, fever. Steven-Johnson Syndrome: Form of immune vasculitis induced by sulfonamides. May be fatal. Symptoms: Erythema multiforme, arthritis, nephritis, CNS abnormalities, myocarditis. TYPE-IV : Contact dermatitis caused by topically-applied drugs or by poison ivy.

33. Drug Toxicity Drug Toxicity : dose-dependent adverse response to a drug. Organ-Directed Toxicity: Aspirin induced GI toxicity (due to prostaglandin blockade); Epinephrine induced arrhythmias (due to beta-agonist); Propanolol induced heart-block (due to beta-antagonist); Aminoglycoside-induced renal toxicity; Chloramphenicol-induced aplastic anemia . Neonatal Toxicity: Drugs that are toxic to the fetus or newborn. Sulfonamide-induced kernicterus;Chloramphenicol-induced Grey-Baby Syndrome; Tetracycline -induced teeth discoloration and retardation of bone growth.

34. Teratogens TERATOGENS : Drugs that adversely affect the development of the fetus: especially dangerous during organogenesis (3 rd to 8 th week) Thalidomide : Antifolates such as Methotrexate . Phenytoin : Malformation of fingers, cleft palate. Warfarin : Hypoplastic nasal structures. Diethylstilbestrol: Oral contraceptive is no longer used because it causes reproductive cancers in daughters born to mothers taking the drug. Aminoglycosides, Chloroquine: Deafness

35. Idiosyncrasy Drug Idiosyncrasies : An unusual response to a drug due to genetic polymorphisms, or for unexplained reasons. Isoniazid: N -Acetylation affects the metabolism of isoniazid Slow N -Acetylation : Isoniazid is more likely to cause peripheral neuritis. Fast N -Acetylation : Some evidence says that Isoniazid is more likely to cause hepatotoxicity in this group. However, other evidence says that age (above 35 yrs old) is the most important determinant of hepatotoxicity. Alcohol can lead to facial flushing, or Tolbutamide can lead to cardiotoxicity, in people with an oxidation polymorphism.

36. Drug Idiosyncrasies Succinylcholine can produce apnea in people with abnormal serum cholinesterase. Their cholinesterase is incapable of degrading the succinylcholine, thus it builds up and depolarization blockade results. Primaquine, Sulfonamides induce acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase deficiency . They have an inability to regenerate NADPH in RBC's ------> all reductive processes that require NADPH are impaired. Note that this is Acute Hemolytic Anemia, yet it is not classified as an allergic reaction -- it is an idiosyncrasy when caused by sulfonamides or primaquine. Other anemias are Type-II hypersensitivity reactions. G6PD deficiency is most prevalent in blacks and Semites. It is rare in Caucasians and Asians. Barbiturates induce porphyria (urine turns dark red on standing) in people with abnormal heme biosynthesis. Psychosis, peripheral neuritis, and abdominal pain may be found.

37. Tolerance Pharmacokinetic Tolerance : Increase in the enzymes responsible for metabolizing the drug. e.g. Warfarin doses must be increased in patients taking barbiturates or phenytoin, because these drugs induce the enzymes responsible for metabolizing warfarin. Pharmacodynamic Tolerance : Cellular tolerance, due to down-regulation of receptors, or down-regulation of the intracellular response to a drug. Physiologic Tolerance : Two agents yield opposite physiologic effects.

38. Tolerance Competitive Tolerance : Occurs when an agonist is administered with an antagonist. Example: Naloxone and Morphine are chemical antagonists, and one induces tolerance to the other. Tachyphylaxis (Refractoriness / Desensitization) – progressive reduction in drug effect due to receptor desensitization Homologous – decrease in number of receptors Heterologous – decreased signal transduction e.g. Tyramine can cause depletion of all NE stores if you use it long enough, resulting in tachyphylaxis.

39. Habituation & Addiction Habituation – getting used to a drug such that one becomes emotionally dependent on the drug Addiction – true physical as well as emotional dependence on a drug; will need pharmacologic support during withdrawal

40. Thank You

41. pharmacogenomics